Guidance for Industry
Content and Format of Chemistry, Manufacturing and Controls Information
and Establishment Description Information for a Vaccine or Related Product
[PDF version of this document]
Additional copies of this guidance document are available from:
Office of Communication, Training and Manufacturers Assistance, (HFM-40)
Center for Biologics Evaluation and Research (CBER)
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
(Tel) 1-800-835-4709 or 301-827-1800
(Internet) http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
January 1999
TABLE OF CONTENTS
GENERAL INFORMATION
- BACKGROUND
- DEFINITIONS
PART 1 - CHEMISTRY, MANUFACTURING AND CONTROLS SECTION
- DRUG SUBSTANCE
- Description and Characterization
- Description
- Characterization
- Physicochemical Characterization
- Biological Activity
- Manufacturer
- Identification
- Floor Diagram(s)
- Manufacture of Other Products
- Contamination Precautions
- Method of Manufacture
- Raw Materials
- Flow Charts
- Detailed Description
- Animal Sources (including fertilized avian eggs)
- Virus Sources
- Cellular Sources
- Microbial Cells
- Animal Cells
- Genetic Constructs and Recombinant Cell Lines
- Cell Bank System
- Cell Growth and Harvesting
- Purification and Downstream Processing
- Inactivation
- Purification
- Stability Processing
- Detoxification
- Synthetic Drug Substance
- Synthetic Peptides
- Conjugates and Modified Drug Substance
- Batch Records
- Process Controls
- In-process Controls
- Process Validation
- Propagation
- Harvest
- Inactivation
- Purification
- Microbiology
- Control of Bioburden
- Manufacturing Consistency
- Reference Standards
- Release Testing
- Drug Substance Specifications
- Specifications
- Impurities Profile
- Reprocessing
- Container and Closure System
- Drug Substance Stability
- DRUG PRODUCT
- Composition and Characterization
- Composition
- Drug Substance(s)
- Excipient
- Adjuvant
- Preservative
- Specifications and Analytical Methods for Drug Product
- Description
- Identity
- Purity and Impurities
- Potency
- Manufacturer and Facilities
- Manufacturing Methods
- Drug Product Specifications
- Sampling Procedures
- Specifications and Methods
- Validation Results
- Container and Closure System
- Microbiology
- Lyophilization
- Drug Product Stability
- Stability Protocol
- Stability Data
- Stability Program
- INVESTIGATIONAL FORMULATION
- ENVIRONMENTAL ASSESSMENT
- METHOD VALIDATION
PART 2 - ESTABLISHMENT DESCRIPTION SECTION
- INTRODUCTION
- GENERAL INFORMATION
- SPECIFIC SYSTEMS
- Water Systems
- General Description
- Validation Summary
- Routine Monitoring Program
- Heating, Ventilation, and Air Conditioning Systems (HVAC)
- General Description
- Validation Summary
- Routine Monitoring Program
- Computer Systems
- CONTAMINATION/CROSS CONTAMINATION ISSUES
- Cleaning procedures and validation
- Dedicated Equipment
- Shared Equipment
- Containment features
GUIDANCE FOR INDUSTRY
Content and Format of Chemistry, Manufacturing and Controls Information
and Establishment Description Information for a Vaccine or Related Product
This guidance document represents FDA's current thinking on the content and format of the Chemistry, Manufacturing and Controls
information and Establishment Description information for a
vaccine or related product. It does not create or confer any
rights for or on any person and does not operate to bind FDA or
the public. An alternative approach may be used if such
approach satisfies the requirements of the applicable statute,
regulations, or both. |
GENERAL INFORMATION
- BACKGROUND
In the Federal Register of July 8, 1997, the Food and Drug
Administration announced the availability of Revised Form FDA
356h, "Application to Market a New Drug, Biologic, or an
Antibiotic for Human Use." This document provides guidance on
the content and format of the Chemistry, Manufacturing, and
Controls (CMC) and Establishment Description sections of a
License Application for a vaccine or related product. Reagents
for in vitro diagnostic use are outside the scope of this
document.
Table of Contents
- DEFINITIONS
Vaccine or Vaccine Related Product
A vaccine is an immunogen, the administration of which is
intended to stimulate the immune system to result in the
prevention, amelioration or therapy of any disease or infection.
A vaccine may be a live attenuated preparation of bacteria,
viruses or parasites, inactivated (killed) whole organisms,
living irradiated cells, crude fractions or purified immunogens,
including those derived from recombinant DNA in a host cell,
conjugates formed by covalent linkage of components, synthetic
antigens, polynucleotides (such as the plasmid DNA vaccines),
living vectored cells expressing specific heterologous
immunogens, or cells pulsed with immunogen. It may also be a
combination of vaccines listed above. Prophylactic vaccines are
not currently recognized as specified biotechnology products in
Title 21 Code of Federal Regulations §601.2.
Vaccine related products include in vivo diagnostic antigens,
other microbial derived proteins such as asparaginase or toxins
such as botulinum toxin. A diagnostic antigen is a crude or
purified fraction isolated from microbial culture and intended
for in vivo detection of an existing specific immune response,
usually by intradermal or percutaneous skin testing, e.g.,
histoplasmin or coccidioidin.
Drug Substance
The drug substance is the unformulated active (immunogenic)
substance which may be subsequently formulated with excipients
to produce the drug product. The drug substance may be whole
bacterial cells, viruses, or parasites (live or killed); crude
or purified antigens isolated from killed or living cells; crude
or purified antigens secreted from living cells; recombinant or
synthetic carbohydrate, protein or peptide antigens;
polynucleotides (as in plasmid DNA vaccines); or conjugates.
For combination vaccines, each active substance, which will be
pooled, combined with other antigens and formulated, should be
described.
Drug Product
The drug product is the finished dosage form of the product.
The drug product contains the drug substance(s) formulated with
other ingredients in the finished dosage form ready for
marketing. Other ingredients, active or inactive, may include
adjuvants, preservatives, stabilizers, and/or excipients. For
vaccine formulation, the drug substance(s) may be diluted,
adsorbed, mixed with adjuvants or additives, and/or lyophilized
to become the drug product.
Table of Contents
PART 1 - CHEMISTRY, MANUFACTURING AND CONTROLS SECTION
- DRUG SUBSTANCE
Production of a drug substance, whether by fermentation,
cultivation, isolation, or synthesis, usually starts with raw
materials. Subsequent steps of the procedure involve
preparation, characterization and purification of intermediates
eventually resulting in the drug substance. The quality and
purity of the drug substance cannot be assured solely by
downstream testing, but depends on proper control of the
manufacturing and synthetic process as well. Proper control and
attainment of minimal levels of impurities depends on:
- appropriate quality and purity of the starting materials,
including the seed organisms, and reagents;
- establishment and use of in-process controls for intermediates;
- consistent adherence to validated process procedures; and
- adequacy of the final (release) control testing of the drug
substance.
- Description and Characterization
This section should be completed for each drug substance
identified as being present in the final drug product. For
combination vaccines, referencing the approved license
application may be acceptable.
- Description
This section should contain a clear description of the drug
substance. The biological name (including strain and/or clone
designation) or chemical name, including any established USAN
name, should be provided. The description should also include
the source of the cells, including microbes, from which the drug
substances were derived, the active components of the cell
fractions or purified antigens, and the physical and chemical
properties of the synthetic drug substance. Any chemical
modification or conjugation of the drug substance should be
described in detail. Also, a list of any inactive substances,
which may be present in the drug substance, should be provided.
- Characterization
This section should contain a description of all analytical
testing performed to characterize the drug substance with
respect to identity, purity, potency, and stability. (See
references 2, 3, 7, 11-17, 19, 21). Test results should include
actual data such as tabular data, legible copies of
chromatograms or spectra, photographs of gels or immunoblots,
actual histograms of cytometric analysis, or other appropriate
formats. Data should be well organized and fully indexed to
enable easy access. Results for quantitative assays should be
presented as actual data, not generally as "Pass" or "Fail."
Some tests listed below may not be necessary or applicable for
all substances.
- Physicochemical Characterization
In general, characterization may include, but is not limited to
the following:
- UV/visible or mass spectrometry;
- amino acid analysis;
- amino acid or nucleic acid sequencing;
- carbohydrate analysis and, if appropriate, sequencing
- peptide mapping;
- determination of disulfide linkage;
- Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis
(SDS-PAGE) (reduced and non-reduced);
- isoelectric focusing (1D or 2D);
- various chromatographic methods such as HPLC, GC, LC, or thin layer chromatography;
- nuclear magnetic resonance spectroscopy; and/or
- assays to detect related proteins including deamidated,
oxidized, processed, and aggregated forms and other variants,
such as amino acid substitutions and adducts/derivatives, and
other process contaminants such as sulfhydryl reagents, urea,
residual host proteins, residual DNA, and endotoxin.
Additional physicochemical characterization may be required for
modified drug substances such as conjugates, multiple antigen
peptides (MAP), or those undergoing further chemical or
enzymatic modifications. The information provided should include
the degree of derivatization or conjugation, the amount of
unmodified substance, removal of free materials (e.g., toxins,
linkers, etc.), and the stability of the modified substance.
- Biological Activity
Further characterization of vaccines may include, but is not
limited to the following:
- specific identity testing such as Western blot analysis or
ELISA;
- cytometric analysis;
- neurovirulence testing, if appropriate;
- serotyping;
- electrophoretic typing;
- inactivation studies;
- neutralization assays; and
- titrations.
- Manufacturer
- Identification
A description and results of all relevant in vivo and in vitro
biological testing (bioassays) performed on the manufacturer's
reference standard lot or other relevant lots to demonstrate the
potency and activity(ies) of the drug substance should be
provided. This section should include a complete description of
the protocol used for each bioassay, the control standards used,
the validation of the inherent variability of the test, and the
established acceptance limits for each assay. The
characteristics of specific antibodies used in the
immunochemical or serological assays should also be included.
- Floor Diagram(s)
For each manufacturing location, a simple floor diagram of the
general layout of the facilities, which traces the drug
substance through the manufacturing process should be included.
This diagram need not be a detailed engineering schematic or
blueprint, but rather a simple drawing that clearly depicts the
relationship of each manufacturing area, suite, or room to the
others. The uses made of adjacent areas that are not the
subject of the application should also be included. The
diagrams should be sufficiently clear to enable visualization of
the production flow and to identify adjacent operations that may
create particular concerns, e.g., the proximity of live viral
cultures to inactivated intermediates or final products,
segregation of animal facilities, etc. Room numbers or other
unique identifiers should be clearly indicated. Reference can
be made to the manufacturing flow chart in section I.C.2.
- Manufacture of Other Products
A comprehensive list of all additional products that are
manufactured or manipulated in the same areas used to produce
the drug substance that is the subject of this application
should be provided. This section should include a brief
description of the type and developmental status of the
additional drug substances/products and indicate the areas into
which these other products will be introduced, whether on an
ongoing or campaign basis, and what manufacturing steps will be
performed in the multiple-use area(s). Also, the applicant
should indicate whether the production of other products will
utilize the same product contact equipment and, if so, how that
equipment will be cleaned and validated between operations for
the manufacturing of different products. Data should be
provided for the validation and cleaning in the appropriate
section.
- Contamination Precautions
For all areas in which operations for the preparation of cell
banks and product manufacturing are performed, including areas
for the handling of animals used in production, the following
information concerning precautions taken to prevent
contamination or cross-contamination, should be provided:
- air quality classification of a room or area in which an
operation is performed, as validated and measured during operations;
- a brief, narrative description of the procedures and/or
facility design features for the control of contamination, cross contamination, and containment (air pressure cascades, segregation of operations and product, etc.) - this is of particular importance for multi-use areas or for work with live
organisms;
- general equipment design description, e.g., does design
represent an open or closed system or provide for a sterile or
non-sterile operation; and
- a description of the in-process controls performed to prevent
or to identify contamination or cross contamination. The manipulation of more than one cell line in a single area, or the use of any piece of equipment for more than one cell line, should be indicated and measures to ensure prevention of cross contamination should be discussed.
- Method of Manufacture
This section should be completed for each drug substance
described in I.A. A detailed description of the manufacturing
and controls should be provided to demonstrate proper quality
control and prevention of possible contamination with
adventitious agents. The inclusion of a list of all relevant
SOPs is recommended; however, actual copies of the SOPs are not
required.
- Raw Materials
A list of all materials (culture media, buffers, resins for
peptide synthesis, chemicals, columns, etc.) used in the
manufacture of the drug substance, and their tests and
specifications, or reference to official compendia, should be
provided. For purchased materials, representative certificates
of analysis from the supplier(s) and/or manufacturer's
acceptance criteria should be provided. Redundant testing at
the purchasing manufacturer may not be necessary if the testing
methods at the vendor are approved by the purchasing
manufacturer. Custom reagents, such as monoclonal antibodies,
enzymes, other proteins, uncommon amino acids and derivatives,
or glycolipids, used in purification or production of the drug
substance, should be described in detail, including
identification of the vendor/supplier, specificity, and origin,
including the manufacturing scheme, if applicable (references 3,
11, 14, 16). Results of adventitious agent testing of raw
materials used in propagation, e.g., serum, trypsin, should be
provided. Process gases (compressed air, carbon dioxide,
nitrogen) and water are considered raw materials. This list
should be referenced in parts of the Application which provide
detailed descriptions of the use of each component (see I.C.4,
Batch Records).
- Flow Charts
In this section, a complete visual representation of the
manufacturing process flow should be provided for each drug
substance. For multiple drug substances prepared from a single
strain, a common flow chart is acceptable, through the
propagation and harvest cycle, with indications of where the
processing diverges. This flow chart should show the steps in
production, equipment and materials used, room or area where the
operation is performed (may reference diagrams in other sections
of the application), and a complete list of the in-process
controls and tests performed on the product at each step. In-
process holding steps should be included, with time and
temperature limits indicated. For chemical synthesis, a flow
chart should include all the steps in a general synthesis cycle
with other specific steps, such as fragment condensation or
peptide cleavage, indicated. This diagram should also include
information (or be accompanied by a descriptive narrative) on
the methods used to transfer the product between steps, (e.g.,
open transfers under laminar flow units). Such transfers should
be described for movement of product between equipment, areas,
rooms, buildings and sites. Manufacturing steps which are
computer controlled should be identified. Reference may be made
to other sections of the application for more detailed process
information. If equipment is dedicated to specific areas or
products, it should be identified.
- Detailed Description
- Animal Sources (including fertilized avian eggs)
Detailed information on any animals used for the propagation of
microorganisms, or production of recombinant proteins (reference
12), for use as vaccines should include, but is not limited to:
- the species and age of the animals;
- the health status of the animals, e.g., specific pathogen free;
- the results of adventitious agent screening;
- the animal husbandry practices, e.g., quarantine procedures, used to ensure the suitability of the animals;
- the veterinary and laboratory monitoring used to ensure the suitability of the animals;
- a description of the inoculation of the animals; and
- a description of the tissues harvested and the method of
harvest.
- Virus Sources
This section should include a detailed description of the virus
seed used for vaccine production. The information submitted
should include, but is not limited to:
- the original source of the virus
- the passage history of the virus strains
- details of the seed lot system
- the culture techniques for virus seed maintenance
- Cellular Sources
For the purposes of this document, cell substrate refers to
microbial cells, or cells or cell lines of animal (insect, as
well as human and other mammalian) origin (references 13, 21).
Cell seed lot systems are frequently adopted for cells or cell
lines, whether they are used as vaccine components (whole cells
or subunits), or as the cell substrate for propagation of
viruses, recombinant DNA products, or polynucleotide vaccine
constructs. Details of the cell seed lot system should be
submitted as explained in iv. of this section. The history and
general characteristics of the cell lines should be provided.
All specific procedures used to generate the cell substrate
should be well documented and submitted as outlined in the
following sections. These may include, for example, cell
fusion, selection, transfection, colony isolation, cloning, gene
amplification, and adaptation to specific culture conditions or
media. The growth pattern and morphological appearance of the
cell lines, from the master cell bank to the end-of-production
cells, should be submitted. A thorough discussion of the
adventitious agent profile of any cell substrate should be
provided.
- Microbial Cells
This section should contain a description of the species,
strain and known genotypic and phenotypic characteristics of the
microorganism from which the drug substance is derived.
Microbial cells and their derivatives used as the vaccine drug
substance include whole cell vaccines (live or killed), crude
lysate or purified immunogens, recombinant DNA products,
conjugates, and plasmid DNA vaccines.
The history and characteristics of each strain used to produce
the product and a complete strain description should be
provided, including:
- origin of isolate;
- species;
- biochemistry (fermentation profile, etc.);
- strain identifier and specific identifying characteristics
(serotype, etc.);
- virulence (attenuation method, if performed);
- genetic characterization, if known (markers, inserts,
deletions, etc.);
- plasmids; and
- genetic stability.
- Animal Cells
Cells of animal origin may harbor adventitious agents and
consequently pose a potentially greater risk to humans if not
properly controlled(reference 21). The measures taken to
remove, inactivate, or prevent contamination of the product from
any adventitious agent present in the cell substrate should be
described.
Primary Cells
This category generally includes the primary cells and those
used within the first passage after establishment from the
tissue of origin. Consequently, primary cells may not be
amenable to the establishment of cell banks. A discussion of
the rationale for the use of primary cells should be provided.
The information submitted for each primary cell line used should
include, but is not limited to:
- the species and age of the animals and the source tissue from which the cells are derived;
- the health status of the animals from which the cells are
derived, e.g., specific pathogen free;
- the animal husbandry practices (quarantine, etc.) used to
ensure the suitability of the animals;
- the veterinary and laboratory monitoring used to ensure the suitability of the animals;
- a description of the preparation of primary cell substrates; and
- an explanation of the concurrent testing done to demonstrate the absence of adventitious agents and the results of those tests.
Cell Lines
The production substrate may consist of a continuous cell line
or diploid cell strain of human or animal origin. For human
cell substrates, the source of cells should be clearly
described, including the materials and methods used, the tissue
or organ of origin, ethnic and geographical origin, age, gender
and general physiological condition. The health or medical
history of the donor, if known, should be provided along with
the results of any tests for pathogenic agents. For animal cell
lines, relevant descriptions of the source may include species,
strains, breeding conditions, tissue or organ of origin,
geographical origin, age, gender, and general physiological
condition of the original donor. Testing for detection of
adventitious agents should be undertaken with consideration of
the possible agents which may be present in the cells. Results
of all testing should be included.
- Genetic Constructs and Recombinant Cell Lines
For recombinant DNA (rDNA) derived products and rDNA-modified
cell substrates, detailed information should be provided
regarding the host cells, and the source and function of the
component parts of the recombinant gene construct (references 7,
13-16, 19, 21), including:
Host Cells
A description of the source, relevant phenotype, and genotype
should be provided for the host cell used to construct the
biological production system. The results of the
characterization of the host cell for phenotypic and genotypic
markers, including those that will be monitored for cell
stability, purity, and selection should be included.
Gene Construct
A detailed description of the gene which was introduced into
the host cells, including both the cell type and origin of the
source material, should be provided. A description of the
method(s) used to prepare the gene construct and a restriction
enzyme digestion map of the construct should be included. The
complete nucleotide sequence of the coding region and regulatory
elements of the expression construct, with translated amino acid
sequence, should be provided, including annotation designating
all important sequence features.
Vector
Detailed information regarding the vector and genetic elements
should be provided, including a description of the source and
function of the component parts of the vector, e.g. origins of
replication, antibiotic resistance genes, promoters, enhancers.
A restriction enzyme digestion map indicating at least those
sites used in construction of the vector should be provided.
The genetic markers critical for the characterization of the
production cells should be indicated.
Final Gene Construct
A detailed description should be provided of the cloning
process which resulted in the final recombinant gene construct.
The information should include a step-by-step description of the
assembly of the gene fragments and vector or other genetic
elements to form the final gene construct. A restriction enzyme
digestion map indicating at least those sites used in
construction of the final product construct should be provided.
Cloning and Establishment of the Recombinant Cell Lines
Depending on the methods to be utilized to transfer a final
gene construct or isolated gene fragments into its host, the
mechanism of transfer, copy number, and the physical state of
the final construct inside the host cell (i.e. integrated or
extrachromosomal), should be provided. In addition, the
amplification of the gene construct, if applicable, selection of
the recombinant cell clone, and establishment of the seed should
be completely described.
- Cell Bank System
A description of the cell banking procedures used should be
provided, including:
- the banking system used;
- the size of the cell banks;
- the container and closure system used;
- a detailed description of the methods, reagents and media
used for preparation of the cell banks;
- the conditions employed for cryopreservation and storage;
- in-process controls; and
- storage conditions.
A description should be provided of the procedures used to
avoid microbial contamination and cross-contamination by other
cell types present in the facility, and the procedures that
allow the banked cells to be traced. A discussion of
precautions taken to prevent any catastrophic event that could
render the cell banks unusable and to ensure continuous
production of vaccines, for example, storage of cell banks in
multiple freezers or at different sites, should be included.
The cell bank system generally consists of two tiers: a Master
Cell Bank (MCB), and a Working Cell Bank (WCB) generated from
the MCB for vaccine manufacturing. In some instances, another
tier of 'Primary Cell Bank' may be established which allows the
manufacturers to perform extensive testing on a pool of
cryopreserved primary cells prior to their usage in vaccine
production.
Master Cell Bank
The cells comprising the MCB should be identified and a
complete history and characterization of the MCB should be
provided, including, as appropriate for the given cells:
- the biological or chemical method used to derive the cell bank;
- biochemistry (cell surface markers, isoenzyme analysis,
specific protein or mRNA, etc.);
- specific identifying characteristics (morphology, serotype,
etc.);
- karyology and tumorigenicity;
- virulence markers;
- genetic markers;
- purity of culture; and
- media and components (e.g., serum).
For recombinant products, the cell substrate used to establish
the MCB is the transfected cell containing the desired genetic
construct which has been cloned from a single cell progenitor.
For non-recombinant products, the cell substrate is the cell
from the parental cell line chosen for preparation of the MCB
without further modification. For a diploid cell line the
population doubling level chosen for the MCB should be given.
Working Cell Bank
This section should contain a description of the procedures
used to derive a WCB from the MCB. The description should
include the identification system used for the WCB as well as
the procedures for storage and cataloging of the WCB. The
assays used for qualification and characterization of each new
WCB should be included with the results of those assays for the
WCB currently in use. If applicable, a description of animal
passage of the WCB performed to assure the presence of virulence
factors which are protective antigens should be supplied. This
section should also contain a description of the methods and
procedures used to assure culture purity and identity.
End of Production Cells (EPC)
For r-DNA derived drug substances, a detailed description of
the characterization of the EPC that demonstrates that the
biological production system is consistent during growth should
be provided. The results of the analysis of the EPC for
phenotypic or genotypic markers to confirm identity and purity
should be included. This section should also contain the
results of testing supporting the freedom of the EPC from
contamination by adventitious agents. The results of
restriction enzyme analysis of the gene constructs in the EPC
should be submitted. Further guidance can be obtained from the
ICH document on "Analysis of the Expression Construct in Cells
Used for Production of R-DNA Derived Protein Products".
Characterization and Testing of Cell Banks
Detailed information on the characterization and testing of
banked cell substrates should be submitted (references 7, 13-
16). This should include the results of testing to confirm the
identity, purity, and suitability of the cell substrate for
manufacturing use. Relevant tests should be described in the
Application, along with the results of the testing. In general,
the methods described in Section I.A.2.a. are considered
adequate tests to confirm the identity and purity. For metazoan
cells, results of tests for the presence of bioburden (bacteria
and fungi) and mycoplasma should be submitted for the MCB and
WCB. The results of virus testing of metazoan cell substrates
to detect possible contaminating viruses, using appropriate
screening tests designed to detect a wide spectrum of viruses
and relevant specific tests based on the cultivation history of
the cell line, should be submitted. Further guidance may be
obtained from the "Points to Consider in the Characterization of
Cell Lines Used to Produce Biologicals, 1993."
- Cell Growth and Harvesting
This section should contain a description of each of the
following manufacturing processes, as appropriate. The
description should contain sufficient detail to support the
consistency of manufacture of the drug substance. It is
understood that all of the processes listed below may not be
performed on every drug substance, or be performed in the order
given. A description of the assignment of batch numbers and how
each batch of a stabilized intermediate containing multiple drug
substances can be related to its component harvests and batches
of individual drug substances should be included.
Propagation
This section should contain descriptions of:
- each step in propagation from retrieval of the WCB to culture harvest (stages of growth);
- the media used at each step (including water quality), with details of their preparation and sterilization;
- the inoculation and growth of initial and sub-cultures,
including volumes, time and temperature of incubation(s);
- how transfers are performed;
- precautions taken to control contamination;
- in-process testing which determines inoculation of the main culture system;
- in-process testing to ensure freedom from adventitious
agents, including tests on culture cells, if applicable;
- the nature of the main culture system including operating
conditions and control parameters (e.g., temperature of
incubation, static vs. agitated, aerobic vs. anaerobic, culture
vessels vs. fermenter, volume of fermenter, or number and volume
of culture vessels);
- the parallel control cell cultures, if applicable, including number and volume of culture vessels;
- induction of antigen, if applicable; and
- the use of antibiotics in the medium and rationale, if
applicable.
A brief description of all process parameters which are
monitored and a typical growth curve or growth description (see
Process validation, I.D.2) should be provided. A list of in-
process controls and testing for purity, viability, antigen
yields, and phenotypic identity; as well as the time points at
which testing is performed should be included in both the Flow
Chart (Section I.C.2.) and the Batch Records (Section I.C.4.).
A description should be provided of the precautions taken to
control contamination, e.g., during sample removal and
transfers, and whether these are "closed" or "open" procedures.
Harvest
A description of the method(s) used for separation of crude
drug substance from the propagation system (precipitation,
centrifugation, filtration, etc.) should be provided. Brief
descriptions should be given for the following:
- the process parameters monitored;
- the criteria for harvesting;
- the determination of yields; and
- the criteria for pooling more than one harvest, if applicable.
This section should include a working definition of a harvest
"batch." A description should be provided of the precautions
taken to maintain aseptic conditions and prevent contamination
during harvesting. A description of the procedures used to
monitor bioburden (including acceptance limits) or sterility
should be included. If the harvested crude drug substance is
held prior to further processing, a description of storage
conditions and time limits should be provided.
- Purification and Downstream Processing
This section should contain a description of the methods and
materials by which intermediate forms and the final bulk of the
drug substance are separated and concentrated from the cells,
media, solvents or solutions used in the production process.
The description of each step of the purification process should
also include the accompanying analytical tests developed or
adopted by the manufacturer to show identity, purity, and
concentration, and the levels of product related and non-product
related impurities. This is particularly important if the
latter materials are determined to be toxins, carcinogens,
teratogens, or allergens. Antibiotics and other components
(e.g., growth factors, antibodies) used in the culture but
neither required nor specifically intended to be in the final
vaccine product should be removed before use. Procedures to
assure containment and prevention of contamination or cross
contamination should be provided.
- Inactivation (if appropriate)
Descriptions should be provided for:
- how culture purity is verified before inactivation;
- the method(s) and agent(s) used for inactivation;
- the method(s) undertaken to prevent aggregation and assure
homogeneous access of inactivating agent(s).
- the stage in production where inactivation or killing is
performed; and
- the parameters which are monitored.
Verification of the adequacy of and margin of safety achieved
by the method of inactivation or killing should be provided (see
I.D.2., Process Validation).
- Purification (if appropriate)
This section should contain an explanation of the objectives
and rationale for purification of component antigens from crude
harvest. Descriptions should be provided for:
- the methods used, including specialized equipment such as
columns; ultracentrifugation, ultrafiltration, and custom
reagents such as monoclonal antibodies;
- the process parameters monitored;
- the determination of yields;
- in-process testing (e.g., sensitivity and specificity of
ELISA);
- the criteria for pooling more than one batch, if applicable;
- sterility or bioburden monitoring and the precautions taken
to prevent contamination during purification;
- the reuse and/or regeneration of columns and adsorbents; and
- monitoring for residual impurities and leachable reagents.
A list of in-process controls and tests for purity, identity,
and biological activity should be provided. The time points at
which testing is performed should be included in both the Flow
Chart (Section I.C.2) and the Batch Records (Section I.C.4.). A
list of the final acceptance criteria for the purified drug
substance should be provided. If the purified drug substance is
held prior to further processing, a description of the storage
conditions and time limits should be included. Verification of
the stability of the purified substance under the conditions
described should be included (see I.D.2, Process Validation).
- Stability Processing
A description should be provided for any post-purification
steps performed to produce a stabilized intermediate, (e.g.,
adsorption, addition of stabilizers, addition of preservatives,
lyophilization (in bulk), desiccation), and the objectives and
rationale for performing each process. A description of
precautions taken to monitor bioburden and prevent contamination
during these processes should also be given. If the stabilized
intermediate is held prior to further processing, a description
of storage conditions and time limits should be included.
Verification of the stability of the drug substance under the
conditions described should be provided (see I.D.2, Process
Validation).
- Detoxification
For toxoid or toxoid-containing vaccines, the detoxification
procedures should be described in detail for the toxin
component(s):
- the method(s) and agent(s) used for detoxification;
- the stage in production where detoxification is performed; and
- the parameters which are monitored.
Verification of the adequacy of the method for detoxification
should be provided (see I.D.2, Process Validation).
- Synthetic Drug Substance
For the purposes of this guidance, synthetic drug substance
includes: linear or complex synthetic peptides, or modified
synthetic or semi-synthetic immunogens such as lipopeptides,
peptide to carrier protein or polysaccharide to carrier protein
conjugates.
- Synthetic Peptides
The detail of the peptide synthesis including purification
procedures should be provided as outlined in the "Guidance for
Industry for the Submission of Chemistry, Manufacturing, and
Controls Information for Synthetic Peptide Substances".
- Conjugates and Modified Drug Substance
This section of the guidance refers to drug substances derived
from another drug substance or intermediate through chemical or
enzymatic modification, e.g., conjugation of an immunogen to a
carrier molecule, enzymatic or chemical cleavage and
purification of the non-toxic subunit of a toxin, or
derivatization. The modification may change the fundamental
immunogenicity, toxicity, stability, or pharmacokinetics of the
source drug substance. The derived drug substance may include
linking moieties and new antigenic epitopes.
Manufacturing Methods
This section should provide a detailed description of:
- the specifications and acceptance criteria, for the native
drug substance starting materials, which assure suitability for
conjugation or modification;
- the conditions of all reactions and/or syntheses used to
produce a semi-synthetic conjugated molecule, derivatized
molecule, or subunit, including intermediate forms of the
reactants and drug substance; also include the process
parameters which are monitored, in-process controls, testing for
identity and biologic activity, and any post-purification steps
performed to produce a stabilized derived drug substance.
The application should include a description of the methods and
equipment used for separation of unreacted materials and
reagents from the conjugate, derivative, or subunit, and a
rationale for the choice of methods.
Specifications
Specifications should be provided for each modified drug
substance, including identity, purity, potency, physical-
chemical measurements, and measures of stability. If test
results for the derived substance will be reported for final
release of the drug product, a validation report, to include
estimates of variability and upper and lower limits, should be
provided for each specification. Specifications should include
the amount of unreacted starting materials and process reagents
unless their removal has been validated.
- Batch Records
A completed (executed) representative batch record of the
process of production of the drug substance should be provided.
- Process Controls
- In-process Controls
For all in-process testing indicated in the Flow Charts, a
brief description of the sampling procedures and the test
methods used should be provided. For testing performed at
significant phases of production, the criteria for accepting or
rejecting an in-process batch should be specified.
- Process Validation
A summary report, including protocols and results, should be
provided for the validation studies of each critical process or
factor that affects drug substance specifications, i.e., a
decision to accept or reject a batch (see "Guideline on General
Principles of Process Validation, 1987" and references 2, 3, 7,
12, 14, 16, 17). The validation study reports with statistical
rigor should document the variability in each process as it
relates to final specifications and quality.
- Propagation
A growth curve or tabular representation of growth
characteristics for each propagation step, based on historical
performance under specified conditions, should be provided.
Data should be included which demonstrate the efficiency of
induction of antigen production, if applicable. Data should
also be provided showing the stability of genetic markers under
the conditions of propagation, if applicable.
- Harvest
For each method or combination of methods, a tabulation should
be provided of yields, purity, and viability (if applicable) of
the crude harvest, based on historical performance.
- Inactivation
Inactivation or killing curves, or a tabular representation,
based on historical performance should be provided. Validation
of the titration method to measure residual live agents,
including sensitivity in a background of inactivated agents,
should be provided.
- Purification
For each method or combination of methods used, a tabulation of
yields, purity, and biological activity should be provided.
Verification of the removal or dilution of product related and
non-product related impurities, e.g., processing reagents,
endotoxin, contaminating cell proteins or nucleic acids, and
other residual contaminants should be included. A standard
denominator (e.g., international units) should be used to
facilitate comparison through processing, concentration, or
dilution.
- Microbiology
A description and documentation of the validation studies for
any processes used for media sterilization, effectiveness of
preservatives, decontamination, inactivating cells prior to
their release to the environment, if such inactivation is
required, etc., should be provided. If the drug substance is
intended to be sterile, information should be submitted as
described in the "Guidance for Industry for the Submission of
Documentation for Sterilization Process Validation in
Applications for Human and Veterinary Drug Products."
- Control of Bioburden
For each process which is not intended to be sterile,
documentation of the control of extraneous bioburden by a
tabulation of in-process testing for bioburden should be
provided. (Validation of bioburden control techniques may be
described under Item 15 of the Application.) For aseptic
processing, further guidance may be found in the "Guideline on
Sterile Drug Products Produced by Aseptic Processing."
- Manufacturing Consistency
Consistency of the manufacturing process for each vaccine
component should be demonstrated by manufacturing at least
three, preferably consecutive, batches of drug substance. The
establishment and use of reference standards in assuring
consistency in product characteristics should be described.
- Reference Standards
A description of the preparation, characterization, and
stability of primary and working reference standards should be
provided. A detailed description of the procedures to qualify
new lots of reference standards and acceptance criteria for a
new reference standard should be included.
- Release Testing
Release (acceptance criteria) testing results and other (for
information only) characterization data (e.g., certificates of
analysis) for each batch should be submitted.
- Drug Substance Specifications
- Specifications
This section should contain the specifications and tests for
each drug substance. These should include assays for identity,
purity, potency (biologic effect), physicochemical measurements
which predict potency, and where applicable, measures of
stability. For highly purified substances, purity in reference
to the theoretical composition should be presented. In some
cases test results for the stabilized intermediates of component
antigens should be included in the final release of the drug
product. The results of the validation studies for each of
these specifications, including estimates of variability and
upper and lower limits, should be provided. Where appropriate,
potency should be presented relative to the respective U.S.
Reference Standard as defined in 21 CFR 610.20.
- Impurities Profile
This section should include a discussion of the impurities in
the drug substance. The identity and quantity of impurities
should be provided along with the analytical data (gels, elution
profiles, Western blots, etc.) which support the impurities
profile. Impurities that should be characterized and
quantitated include:
- product related impurities (variants or alterations of
antigen occurring during processing or storage)
- Process related impurities
- media components;
- cell substrate proteins or nucleic acids; or
- process reagents which have not been removed by the
purification process (see I.D., Process Controls).
- Reprocessing
This section should include detailed information on any
reprocessing that may be done on each drug substance. The
information provided for each reprocessing procedure should
include:
- a description of the conditions or criteria, determined from
process controls or specifications, which indicate the need for
re-processing;
- a description of the reprocessing step;
- the Standard Operating Procedure for the step;
- a description of any additional or modified in-process
controls or specifications which are included to monitor re-
processing steps;
- a description of the modifications in batch numbers and
documentation of re-processing in the Batch Production Record
(BPR); and
- the evidence derived from validation studies which assures
that product identity, purity, potency, and stability is
preserved for re-processed batches.
- Container and Closure System
A description of the container and closure system, and its
compatibility with the drug substance should be submitted. The
submission should include detailed information concerning the
supplier, address, and the results of compatibility, toxicity
and biological tests. Alternatively, a Drug Master File (DMF)
may be referenced for this information. If the drug substance
is intended to be sterile, evidence of container and closure
integrity for the duration of the proposed expiry period should
be provided.
- Drug Substance Stability
This section should contain information on the stability of the
drug substance and any in-process material at each holding step,
as outlined in "Stability Testing of New Drug Substances and
Products, 10/27/93," "Quality of Biotechnological Products:
Stability Testing of Biotechnological/Biological Products,
11/30/95" and "Guideline for Submitting Documentation for the
Stability of Human Drugs and Biologics, 1987."
Table of Contents
- DRUG PRODUCT
This section should contain information on the final drug
product including all drug substances and excipients in the
final product. If any proprietary preparations or mixtures are
used as components, the information provided should include a
complete statement of composition and other information that
will properly describe and identify these materials. For all
ingredients of human or animal origin, testing results or
certificates of analysis demonstrating their freedom from
adventitious agents should be provided. Appropriate information
may be cross-referenced to those under Drug Substance.
- Composition and Characterization
- Composition
A list should be provided of all components in the drug
product, including drug substance(s) and other ingredients, with
their unit doses and batch quantities specified. For some
inactive ingredients, the quantity may be expressed as percent
or molarity.
- Drug Substance(s)
A list of each drug substance should be provided.
- Excipient
This section should contain a list of all inactive components
with the rationale for the inclusion of each in the final
product. The information provided should include certificates
of analysis, results of analytical testing, or other information
that will describe or identify each excipient. If compendial
excipients are used, citations may be included in lieu of
analytical testing. Excipients may include, but not be limited
to:
- diluents (molarity, pH should be included for these);
- bulking agents;
- adsorbents (other than adjuvants); and
- stabilizers (e.g., sugars, wetting agents).
- Adjuvant
This section should contain a list of the chemical formula and
precise quantity of each adjuvant per unit dose. Whether the
quantity of adjuvant is determined by assay or by calculation
should be indicated and the method used should be described.
- Preservative
Each preservative should be identified by chemical as well as
any trade name or reference to compendial sources. A rationale
should be provided for the inclusion of a preservative in single
dose drug products. The results of the preservative
effectiveness studies should be included or reference may be
made to other files.
- Specifications and Analytical Methods for Drug Product
This section should contain a description of tests and
specifications for all ingredients, if not specified in the Drug
Substance section.
- Description
A qualitative statement describing the physical state
(lyophilized solid, powder, liquid) and color and clarity of the
drug product and other ingredients should be provided.
- Identity
The assays used to establish the identity of the drug product
should be described. The description of each assay should
include an evaluation of its specificity and sensitivity.
- Purity and Impurities
This section should include information on the purity of the
final product including identification and quantitation of
impurities, including degradation products, inherent in the
final dosage form. If impurities are known to be introduced or
formed during the production of the drug product, the acceptable
limits of these impurities should be determined and included in
the specifications.
- Potency
A description should be provided of the potency assay for the
drug product. Information should be submitted on the
sensitivity, specificity, and variability of the assay including
the data from the material used to prepare clinical/preclinical
lots which were used to set the acceptance limits for the assay.
- Manufacturer and Facilities
The name(s) and address(s) of all manufacturers involved in the
manufacture and testing of the drug product including
contractors, and a description of the responsibility(ies) of
each should be submitted. A list of all other products
(research & development, clinical or approved) made in the same
rooms should be provided. See Part 1, Section I. B. of this
document for detailed guidance.
- Manufacturing Methods
This section should include a detailed description of the
manufacturing process flow of the formulated bulk and finished
drug product including the sterilization operations, aseptic
processing procedures, lyophilization, and packaging.
Accompanying this narrative, a flow chart should be provided
that indicates the production step, the equipment and materials
used, the room or area where the operation is performed (may
reference the simple floor diagram) and a listing of the in-
process controls and tests performed on the product at each
step. A Master Production Record (MPR) for the drug product
should be provided, including complete manufacturing
instructions for adsorption (if applicable), formulation,
filling, labeling, and packaging. References may be made to
other sections for more detailed information. Results of
studies validating the compatibility of the components including
the adjuvants and/or preservatives, if applicable, should be
provided. Lot-to-lot consistency of the drug product should be
demonstrated.
- Drug Product Specifications
- Sampling Procedures
The sampling procedures for monitoring a batch of finished drug
product should be included.
- Specifications and Methods
A description of all test methods selected to assure the
identity, purity, strength and/or potency, as well as the lot-to-
lot consistency of the finished product and the specifications
used for the drug product should be submitted. Certificates of
analysis and analytical results for at least three consecutive
batches should be provided.
- Validation Results
The results of studies validating the specificity, sensitivity,
and variability of each method used for release testing should
be provided. Where applicable this should include descriptions
of reference standards and their validation. For analytical
methods in compendial sources, the appropriate citations should
be provided.
- Container and Closure System
A description of the container and closure system, and its
compatibility with the drug product should be submitted.
Detailed information concerning the supplier(s), address(es),
and the results of compatibility, toxicity and biological tests
should be included. Alternatively, a DMF can be referenced for
this information. For sterile product, evidence of container
and closure integrity should be provided for the duration of the
proposed expiry period.
- Microbiology
Information should be submitted as described in the "Guidance
for Industry for the Submission of Documentation for
Sterilization Process Validation in Applications for Human and
Veterinary Drug Products."
- Lyophilization
A validation summary for lyophilization of the drug product
should be given which includes:
- A narrative description of the validation (or protocol);
- Certification that IQ and OQ have been completed;
- A validation data summary;
- Explanation of all excursions or failures; and
- Deviation reports and results of investigations of all
excursions or failures.
- Drug Product Stability
This section should state the proposed expiration dating period
for the drug product and the recommended storage conditions.
The criteria for determining the date of manufacture, from which
the expiration dating period begins, should be defined. For
lyophilized products, a shelf-life after reconstitution should
be proposed. Detailed guidance on stability may be found in
"Stability Testing of New Drug Substances and Products,
10/27/93," "Quality of Biotechnological Products: Stability
Testing of Biotechnological/Biological Products, 11/30/95"
"Guideline for Submitting Documentation for the Stability of
Human Drugs and Biologics, 1987," and "Guidance for Industry:
Stability Testing of Drug Substances and Drug Products," June
1998.
- Stability Protocol
A stability study protocol should be provided which includes,
but is not limited to, testing for:
- potency;
- physicochemical measurements which are potency-indicating;
- moisture, if lyophilized;
- pH, if appropriate;
- sterility or control of bioburden;
- viability of cells, if frozen and thawed;
- pyrogenicity; and
- general safety.
- Stability Data
The summary results which support the proposed expiration
dating period, under recommended conditions, in the final
container and closure system, should be provided. The stability
of each dosage form should be separately documented. For
lyophilized products the data supporting the shelf-life of the
product following reconstitution should be included. If the
drug product is frozen, data supporting the stability of the
product through a stated number of freeze-thaw cycles should be
provided.
- Stability Program
A plan for an on-going stability program should be provided.
This should include the protocol to be used, number of final
lots to be entered into the stability protocol each year and how
such lots will be selected.
Table of Contents
- INVESTIGATIONAL FORMULATION
A discussion of any differences in formulation, manufacturing
process, or site between the clinical trials materials and
commercial production batches of drug substance and drug product
should be submitted. If there are differences, a complete
description of these differences should be included. If an
investigational drug formulation was different from that of the
to-be-marketed finished product, data to support comparability,
bioequivalence and/or pharmacokinetic equivalence of the two
formulations should be provided, if appropriate (reference 9).
If the manufacturing process and/or site was different, data
from appropriate testing to assess the comparability of the
investigational and commercial products should be provided.
Table of Contents
- ENVIRONMENTAL ASSESSMENT
An environmental assessment (EA), as outlined in 21 CFR Part
25, or a request for a categorical exclusion with the basis for
the exclusion, should be submitted. If an EA is appropriate, it
should include a description of the action that is being
considered and should address all the components involved in the
manufacture and disposal of the product.
- METHOD VALIDATION
For all release or acceptance testing performed on the drug
substance(s) or product, information as described in the
"Guideline for Submitting Samples and Analytical Data for
Methods Validation" should be provided.
Table of Contents
PART 2 - ESTABLISHMENT DESCRIPTION SECTION
- INTRODUCTION
In the Federal Register of July 8, 1997, the Food and Drug
Administration announced the availability of Revised Form FDA
356h "Application to Market a New Drug, Biologic, or an
Antibiotic for Human Use." This section provides guidance on
the content and format of information submitted in Section 15,
the Establishment Description section, of a License Application
for vaccines and vaccine related products. The information
contained in this section need not be submitted for recombinant
DNA derived vaccines or synthetic peptide vaccines.
Table of Contents
- GENERAL INFORMATION
For each manufacturing location, a floor diagram should be
included that indicates the general facility layout. The
following information should be provided on each floor diagram
and/or in an accompanying narrative:
- Product, personnel, equipment, waste and air flow;
- An illustration or indication of which areas are served by
each air handling unit; and
- Air pressure differentials between adjacent areas.
Alternatively, this information may be illustrated on the floor
diagram requested in the CMC section. The manufacturing flow
chart requested in the CMC section may also be referenced as
applicable.
Table of Contents
- SPECIFIC SYSTEMS
- Water Systems
The following information on water purification systems for the
production of water for use in manufacturing and rinsing of
product contact equipment, and containers and closures, should
be provided.
- General Description
A general description of the water system(s) should be
submitted, including water source, major components, and a
general discussion of the type of water used for each stage of
processing.
- Validation Summary
A validation summary should be provided containing:
a narrative description of the validation process (or
protocol) including acceptance criteria;
- certification that installation qualification (IQ) and
operational qualification (OQ) have been completed;
- the length of the validation period;
- the parameters monitored and tests performed;
- the frequency of monitoring each point of use during the
validation period;
- a validation data summary; and
- an explanation of all excursions or failures, including
deviation reports and results of investigations.
- Routine Monitoring Program
A narrative description of the routine monitoring program
should be submitted, to include:
- the tests performed;
- the frequency of testing;
- the alert and action limits used; and
- a summary of actions to be taken when limits are exceeded.
- Heating, Ventilation, and Air Conditioning Systems (HVAC)
- General Description
A general description of the HVAC system(s)should be provided
including:
- the number and segregation of air handling units;
- whether air is once-through or recirculated;
- containment features; and
- air changes/hour.
The information required for some of these features is
described below in greater detail in the contamination/cross
contamination section of this document. Reference may be made
to information in the CMC section.
- Validation Summary
A validation summary with the following information should be
provided for the system, which contains:
- a narrative description of the validation process (or
protocol), including the acceptance criteria;
- certification that IQ, OQ and certification of filters has
been completed;
- length of the validation period;
- a validation data summary (validation data should include
Performance Qualification data accumulated during actual
processing); and
- an explanation of all excursions or failures, including
deviation reports and results of investigations.
- Routine Monitoring Program
A narrative description of the routine monitoring program
should be provided including:
- the tests performed and frequencies of testing for viable and
nonviable particulate monitoring parameters;
- viable and nonviable particulate action and alert limits for
production operations for each manufacturing area; and
- a summary of actions to be taken when limits are exceeded.
- Computer Systems
This section should contain information on computer systems
which control critical manufacturing processes. The developer
of the system, i.e., whether in-house or contractor, should be
identified. The information provided should also include a
brief description of procedures for changes to the computer
system. For each of these systems a list of the manufacturing
steps which are computer-controlled should be provided. This
section should also contain a validation summary for each of
these systems, which includes:
- a narrative description of the validation process (or
protocol), including acceptance criteria;
- certification that IQ and OQ have been completed;
- an explanation of the parameters monitored and tests performed;
- a validation data summary;
- an explanation of all excursions or failures; and
- deviation reports and results of investigations for all
excursions or failures.
Table of Contents
- CONTAMINATION/CROSS CONTAMINATION ISSUES
The following information regarding methods to prevent
contamination and cross contamination should be provided to
supplement the information requested in the CMC section of the
application.
- Cleaning procedures and validation
- Dedicated Equipment
A brief description of the cleaning procedures and cleaning
reagents used should be provided. This section should also
contain a certification that the cleaning validation for removal
of product residuals and cleaning agents has been successfully
completed.
- Shared Equipment
This section should contain:
- a brief description of the cleaning procedures and cleaning
reagents;
- a rationale for the cleaning procedures chosen which
addresses their effectiveness for the residual products to be
removed; and
- a validation report describing the cleaning validation
procedures for removal of product residues and cleaning agents.
The report should identify the sampling and analytical methods
used and address their sensitivities and specificities.
- Containment features
This section should contain a description of segregation and
containment procedures for areas, manufacturing operations,
personnel, equipment and waste materials designed to prevent
contamination of products. The features that are employed to
maintain segregation and containment should be discussed. These
features might include but is not limited to:
- air pressure differentials between adjacent manufacturing
areas;
- segregation of air handling units;
- air supply and return (recirculated, once-through, HEPA
filtered out, etc.); and
- use of airlocks
Reference may be made to information in the CMC section.
Table of Contents
APPENDIX A
Guidance
- Guidance for Industry for the Submission of Documentation
for Sterilization Process Validation in Applications for Human
and Veterinary Drug Products, 1994
- Guidance for Industry for the Evaluation of Combination
Vaccines for Preventable Diseases: Production, Testing, and
Clinical Studies, 1997
- Guidance for Industry for the Submission of Chemistry,
Manufacturing, and Controls Information for Synthetic Peptide
Substances, 1994
- Guideline on Sterile Drug Products Produced By Aseptic
Processing, 1987
- Guideline for Submitting Documentation for the Stability of
Human Drugs and Biologics, 1987
- Guideline for Submitting Supporting Documentation in Drug
Applications for the Manufacture of Drug Substances, 1987
- Guideline for Submitting Samples and Analytical Data for
Methods Validation, 1987
- Guidance for Industry for the Submission of Chemistry,
Manufacturing, and Controls Information for Therapeutic
Recombinant DNA-Derived Product or a Monoclonal Antibody Product
for In Vivo Use, 1996
- FDA Guidance Concerning Demonstration of Comparability of
Human Biological Products, Including Therapeutic Biotechnology-
Derived Products, 1996
- Guideline on General Principles of Process Validation, 1987
Points To Consider
- Points to Consider in the Manufacture and Testing of
Monoclonal Antibody Products for Human Use , 1997
- Points to Consider in the Manufacture and Testing of
Therapeutic Products for Human Use Derived from Transgenic
Animals, 1995
- Points to Consider in the Characterization of Cell Lines
Used to Produce Biologicals, 1993
- Points to Consider in the Production and Testing of New
Drugs and Biologicals Produced by Recombinant DNA Technology, 1985
- Supplement to the Points to Consider in the Production and
Testing of New Drugs and Biologicals Produced by Recombinant DNA
Technology: Nucleic Acid Characterization and Genetic Stability,
1992
- Points to Consider on Plasmid DNA Vaccines for Preventive
Infectious Disease Indications, 1996
- Points to Consider in Human Somatic Cell and Gene Therapy,
1991
International Conference on Harmonization (ICH) Guidelines
- Stability Testing of New Drug Substances and Products,
10/27/93
- Analysis of the Expression Construct in Cells Used for
Production of R-DNA Derived Protein Products, 11/29/95
- Quality of Biotechnological Products: Stability Testing of
Biotechnological/Biological Products, 11/30/95
- Viral Safety Evaluation of Biotechnology Products Derived
from Cell Lines of Human or Animal Origin, 11/29/95
- Guidance on Quality of Biotechnological/Biological Products:
Derivation and Characterization of Cell Substrates Used for
Production of Biotechnological/Biological Products, 9/21/98
Table of Contents
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